ZA200603307B

ZA200603307B - Process for preparing substituted 5-amino-pyrazolo-[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines

Info

Publication number: ZA200603307B
Application number: ZA200603307A
Authority: ZA
Inventors: Kuo Shen-Chun; Tran Loc Thanh; Andrew D Jones; Tsai David Jieh-Shyh; Zhang Pengyi
Original assignee: Schering Corp
Priority date: 2003-10-28
Filing date: 2006-04-25
Publication date: 2008-07-30
Also published as: US7601833B2; US20090326241A1; US7223861B2; SI1678182T1; WO2005044819A1; JP4782693B2; DK1678182T3; PT1678182E; DE602004004677T2; US20050090492A1; JP2007509948A; CN101899050A; US20090005559A1; CN1898246B; MXPA06004722A; CA2543431A1; ES2278353T3; CY1106393T1; HK1086008A1; JP2011116795A

Description

PROCESS FOR PREPARING SUB STITUTED 5-AMINO-PYRAZOLO-[4,3-6]-1,2.4-

TRIAZOL €©J[1,5-cIPYRIMIDINES

FIELD OF THE INVENTION

The present invention relates to a process for preparing substituted 5-amino- pyrazolo}4,3-e}-1,2,4-triazolo-[1,5-c}pyrimidine compounds having an aminoatkyl substituent at the 7-position.

BACKGROUND :

Substituted 5-amino-pyrazolo 14,3-e]-1,2,4-triazolo-[1 ,5-c]pyrimidine compounds disclosed in WO 01/922-64 are useful as Aza receptor antagonists in the treatment of central nervous system diseases, in particular Parkinson's disease.

WO 01/92264 discloses processes for preparing 5-amino-2-substituted- pyrazolo[4,3-e}-1,2,4-triazolo-[1,5-c]goyrimidines comprising dehydrative rearrangement of hydrazines. Baral diet al, J. Med. Chem, 41, (1998), p. 2126-2133 disclose formation of a 5-amino-pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidine having a phenylalkyl substituent at the 7-po- sition, wherein the reaction comprises reacting a phenylalkyl-substituted hydrazide with (ethoxymethylene)malonitrile to form a substituted pyrazole. Baraldi et al, [B. Med. Chem., 39, (1996), p. 1164-1171 disclose formation of a 7-substituted 5-aminc-pyrazolo[4,3-€]-1,2,4-triazolo-[1,5-c]pyrimidine by reaction of an alkylated pyrazole with (ethoxymethylene)malonitrile. Both Baraldi et al process use NH.CN to accomplish the final ring closure.

SUMMARY OF THE INVENTION

The present invention relatess to a process for preparing compounds having the structural formula

NH,

PNY

Rr "x =N

SVN,

N= or a pharmaceutically acceptable salt or solvate thereof, wherein

R is R'-furanyl, R'-thienyl, R®-pyridyl, R'-pyridyl N-oxide, R'-oxazolyl,

R'-phenyl, R'-pyrrolyl or cycloalkenyl;

X is C2-Cg alkylene; (CH2)m i \

ET

Y is ~N(RICH2CHN(R®)-, -OCH,CHN(R?)-, (CHz)2"NH-, or (CHzh R* and

Z is R5-phenyl, R>phenylalkyl, R>-heteroaryl, diphenylmethyl, R®-C(O)-,

Q

HN. N= . —C—

R.-SO,-, © or phenyl-CH(OHY)-; or when Q is H ,Zis also phenylamino or pyridylamino; or

Z and Y together are

Re= » N R N— .

N=y 10 RQ =~ = R \} Ps =~ N— \ V/

R'is 1 to 3 substituents independently selected from hydrogen, alkyl, -CF3, halogen, —NOz, -NR™R™, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyt;

R? and R2 are independently selected from the group consisting of hydrogen and alkyl; m and n are independently 2-3;

Qis

N= LG 0m ar

H CN ' OH COCHj.

R* is 1-2 substituentss independently selected from the group consisting of hydrogen and alkyl, or two R* substituents on the same carbon can form =O;

RS is 1 to 5 substitue nts independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkyl-amino, -CF3, -OCFa, acetyl, -NO,, hydroxyatkoxy, alkoxwalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy- alkoxy, alkoxycarbonylalko<y, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO-, alkyl-SOz-alkoxy/, tetrahydropyranyloxy, alkylcarbonyi-alkoxy, alkoxycarbonyl, alkylcarboryloxy-alkoxy, -SOzNH;, or phenoxy; or adjacent R® substituents together are —O-CHz-O-, -O-CH,CH,-O-, -O-CF2-O- or -O-CF,CF2-O- and form a ring with the ca¥bon atoms fo which they are attached;

R® is alkyl, R®-phenyi, R®-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(0)-NH-(C1-Ce)alkyi-, dialkyl-aminomethyl, or (~ alky-0"S0 .

R? is 1-2 groups indiependently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3 and alkoxy-alkoxy;

R'is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, kaydroxy, alkoxy, -CN, -NHo, alkylamino, dialkylamino, -CF3, -OCF3 and -S(O)o-2alkyl;

R'is H or alkyl; ard

R" is alkyl-C(O)- ox alkyl-SOz; comprising a) reacting the hydroxyl group of a pyrazole of formula il

HN rod

N I with an activating aagent in the presence of a base to obtain a compound of formula Ili

HAN on

By I wherein L is a leav ing group, and coupling the compound of formula Ill with a compound of formula IV

Z-Y-H Iv in the presence of a base to obtain a compound of formula V

H2\ CN

Z—Y=X=N_

N? \Y b) treatirmg the compound of formula V with trialkyl orthoformate in the presence= of a catalytic amount of acid to obtain a compound of forms ula VI

NZ OR

CN

Z-Y—X—N wow wherein BR is alkyl; c¢) condensing the compound of formula V1 with a hydrazide of formraula VII

H.NHN-C(O)-R VII in the presence of an acid to obtain a compound of formula Vil

Ne -R

NY

~

Z-Y—X-N ‘NZ vill and hydrolyzing the compound of formula VII to obtain 2 compound of formula BX

N R

HN YY ied

Z-Y—X—N “N7 IX d) cyclizing the compound of formula IX with a cyanating agent selected from the grougp consisting of cyanates and cyanogen halides in the prese=nce of a base to obtain a compound of formula I. in particular, the invention relates to cyclizing a compound of formulla IX with a cyanating agent to obtain a compound of formula I.

DETAILED DESCRIPTION

Preferred compounds of formula | prepared by the claimed processs are those wherein R is R®-furanyl, R'-thienyl, R'-pyrrolyl or R™-phenyl, more prefera bly

R'-furanyl. R' #s preferably hydrogen or halogen.

Another group of preferred compounds is that wherein X is ethyl ene. [(CHan

AN

Y is prexferably (CHW R* wherein Q is —N— or ~CH—, with Q preferably being nitroger. Preferably, m and n are each 2, and R*is H.

A prefered definition for Z is R™-phenyl, R®-heteroaryl, R®-C(O)— or R®-80x-.

R® is preferably H, halogen, alkyl, alkoxy, hydroxyalkoxy or alkoxyalkoxxy. Ris preferably R5—phenyl. Especially preferred are compounds wherein Z Bs R°-phenyl and R® is one substituent selected from the group consisting of alkoxy and alkoxyalkoxy- A preferred alkoxy group is methoxy, with alkoxyalkoxy being more preferred, e.g., methoxyethoxy and ethoxyethoxy; methoxyethoxy is ranost preferred.

In step a, preferred embodiments of the process use a compou nd of formula

IV-A: —

Om

HaCO IV-A.

In step b, the preferred trialkyl orthoformate is triethyl orthofonmate.

Preferred embodiments of the process use 2-furoic hydrazide imn step ¢ (formula Vi) , thus preparing compounds of formula | wherein R is 2-furyl.

Prefered reagents for the cyclization in step f are cyanates.

In a p referred aspect, the process of the invention comprises the preparation of compounds of the formulas I-A to I-C: re

NZN-N

OO

H;CO I-A

NHa

Aen © ~~ a dy TY od In N= LB

NZ NN A

HaC RP 30, I \ — o—{ )-N_N N 1I—C in a most preferred aspect, the process of the invention comprises the preparation of a compound of formula I-A comprising: a) reacting the hydroxyl group of a pyrazole of formula li "a LCN

HO-X—N_ PP

N 1] with methanesulfonyl chloride in the presence of a base to obtain a compound of formula lila

HoN “NON

Ne

MsO N a; aand coupling the compound of formula Illa with a compound of formula IVa 0 pam NH ~~ \—/

MeO IVa im the presence of a base to obtain a compound of formuala Va .

HN

~ /\ N oH n— NZ ~~ \_/

MeO Va b) treating the compound of formula Va with trimethyl orthoformate in the presence of a catalytic amount of an acid to obtain a compound of formula Via

Paes

Ng ~ = /\ NC

ATE

Vand /

MeO Via «) condensing the compound of formula Via with a hydrazide of formula Vlla

Ho JN rai 0) Viia :

in the presence of an acid to obtain a compound of formula Villa

SAD da

AO Ne

MeO Villa and hydrolyzing the compound of formula Villa to obtain a compoundl of formula IXa .N

Ha

OO

MeO iXa d) cyclizing the compound of formula 1Xa with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the preserce of a base.

Starting materials of formula Il are known in the art (see, for example, Baraldi et al, J. Med. Chern., 39, (1996), p 1165).

In step a, thwe hydroxyl group on the compound of formula Il is reacted with an activating agent comprising a leaving group, L, wherein L is an optionally smbstituted alkylsulfonyl- or arylsulfonyl- group. When L is a sulfonyl group such as methanesulfonyl, Erifluoromethanesulfonyl, ethanesulfonyl, benzenesulfonyl, p-toluenesulfonyi, p-bromobenzenesulfonyl or m-nitrobenzene-sulfonyl, typically the

L-containing activating agent is an L-halide, e.g., methansulfonyl chloride. A preferred leaving group is methanesuifonyl.

The reactiosn is carried out in a non-protic organic solvent such as CHiCN at a temperature of ab-out -20°C to about 0°C, most preferably at about 0°C. A bout 1-2, preferably about 1-1.5 equivalents of activating reagent are used, and abosut 1-2, preferably about 4-1.5 equivalents of an organic base such as diisopropyleathyl amine.

The activated connpound of formula Ill is not isolated.

The compound of formula Ii is coupled with an amine of formula IV. The reaction is carried out in the presence of an inorganic base such as NaOHE or K2CO,,

at a temperature range of -50°C to about 150°C, preferably at about -20°C to about 0°C, most preferab ly at about -10°C. About 1-2 equivalents of base are u sed.

In step b, thee amino substituent on the compound of formula V is converted to the imidate by treatment with 1-10 equivalents of a trialkyl orthoformate irs a non- protic organic solveant such as toluene at reflux temperature in the presersce of a catalytic amount off acid (e.g., about 1 mol %). Any organic or inorganic acid can be used, but a preferred acid is p-tolunensulfonic acid. A preferred trialkyl o-rthoformate is trimethyl orthofosrmate.

The imidate of formula VI is then condensed with a hydrazide of fomula Vil in step c. The reaction Is carried out in an organic solvent such as toluene ata temperature ranges of about -20°C to about 110°C in the presence of 1-2 equivalents of an acid such ass isobutyric acid.

The compound of formula Vill is then hydrolysed under acidic comditions to form the ring-opened compound of formula IX. The acid can be a mineral acid or an alkyl or aryl sulforic acid; the concentration of acid is not critical, but is preferably at 2.5%. The reaction is carried out at temperature range of about room temperature to about 110°C.

In step d, the compound of formula IX is cyclized by treatment with a cyanating agent selected from the group consisting of cyanates and cyanogen hal3des to obtain a compound of formula |. The reaction is conducted in an organic solvent such as

CH3CN or tetrahydrofuran (THF) at a ratio of 4-20 wiv, preferably about &wiv, optionally in the presence of water (0 to 30% v/v, preferably about 10%. An inorganic base (e.g, Na;CO3, NaHCO3, KHCO3, NaOH, KOH, K3POs, K=HPO.,

NasPO,, Na,HPO.) or organic base (e.g., trialkylamine) is added a ratio= of about 0.2 to 0.5 equivalents. The reaction is carried out at a temperature of abount 35°C to reflux, preferably- about 53°C to about 58°C. 1-2 equivalents of the cyamating agent are used, wherei n the cyanating agent is a cyanate or a cyanogen halicle. Cyanates (i.e., compoundss of the formula Ar-OCN, wherein Ar is an optionally substituted aromatic moiety are exemplified by substituted phenyl cyanates such aas 2-methoxypheny~! cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl c=yanate and bisphenol A cyarate. Cyanogen halides are exemplified by cyanogen Eoromide and cyanogen chloride. Cyanates are preferred, with 2-methoxyphenyl cya nate being most preferred. The reaction is quenched by the addition of an aqueows solution of an inorganic base (e.g., Na;COs, NaHCO, KHCO3, NaOH, KOH, KaPOs, K2HPO4,

NazPO4, NasHPO,).

The present process provides an advantage over the procedures previously reported in the art. Known processes used highly toxic and corrosive NH2CN to cyclize the ring, while the present process uses a cyanating agent such as a cyanate (e.9., 2-methoxyphenyt cyanate) or @ cyanogen halide (e.g., cyanogen bromide).

Furthermore, the preferred cyanatin g agents, cyanates, are preferable to the relatively more toxic cyanogen halides. Also, the temperature range for conducting the second part of step a of this invention is about 150°C lower than that used in literature preparations. The present inventiors therefore, allows for large scale production and high yields using milder conditions.

As used herein, "alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 6 carbon atoms in the chain.

Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain- Alkylene, referring to a divalent alkyt group, similarly refers to straight or branched chains. rAlkoxy" means an alkyl-O- -group in which the alkyl group is as previously described, unless otherwise noted_ Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxcy, iSOpropoxy, n-butoxy and heptoxy. The bond to the parent moiety is through the ether oxygen. "Cycloalkyl” means a non-a romatic ring system comprising about 3 to about 6 carbon atoms. Non-limiting exampsles of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl and cyclohexyl, and the like. Cycloalkylene refers to a divalent cycloalkyl group. Cycloallkkenyl refers to a C4-Ce cycloalkyl! ring comprising one double bond. “Heteroaryl” means a single ring, bicyclic or benzofused heteroaromatic group of 5 to 10 atoms comprised of 2 to 9 carbon atoms and 1 to 4 heteroatoms independently selected from the garoup consisting of N, O and S, provided that the rings do not include adjacent oxygen and/or sulfur atoms. N-oxides of the ring nitrogens are also included. Exarwples of single-ring heteroaryl groups are pyridyl, oxazolyl, isoxazolyl, oxadiazolyl, fuiranyl, pyrrolyl, thienyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isothiazolyl, theiadiazolyl, pyrazinyl, pyrimidyl, pyridazinyl and triazolyl. Examples of bicyclic hetercaaryl groups are naphthyridyl (eg.,1,50r 1,7), imidazopyridyl, pyrido[2,3Jimidazolyl.. pyridopyrimidinyl and 7-azaindolyl. Examples of benzofused heteroaryl groups are in dolyl, quinolyl, isoquinolyl, phthalazinyl, benzothienyl (i.e., thionaphthenyl), beenzimidazolyl, benzofuranyl, benzoxazolyl and benzofurazanyl. All positional isomers are contemplated, e.g., 2-pyridyl, 3-pyridyt and 4-pyridyl. R5-substituted heteroaryl refers to such groups wherein substitutable ring carbon atoms have a substituent as defined above. "Alkyithio” means an alkyl-S— group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methyithio, ethyithio, and i-propyithio. The bond to the parent moiety is through the sulfur. "Alkylsulfonyl” means an alkyi-S(O2) group. The bond to the parent moiety is through the sulfonyl. "Alkylsulfinyl” means an alky/i-S(O)- group. The bond to the parent moiety is through the sulfinyl. “Carbonyl” means a —C(O)- moiety, e.g., alkoxycarbonyl refers to an alkoxy-

C(0)- group (i.e., alkyt-O-C(O)-). “Acetyl” means —C(O)CHa.

Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation. , for example when one or more solvent molecules are incorporated in the crystal latti ce of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methhanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H 20.

Certain compounds of the Invention may exist in different stereoisomeric formss (e.g., enantiomers, diastereoisom ers and atropisomers). The invention contemplates all such stereoisomers both in puwe form and in mixture, including racemic mixtures.

Certain compounds will be acidic in nature, e.g. those compounds which possess a carboxyl or phenolic hydroxy! group. These compounds may form pharmaceutically acceptable salts. Examples of such salts may include sodium, potassium, calcium, aluminum, gold and silver salts. Also contemplated are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylgiu camine and the like.

Certain basic compounds also form pha_rmaceutically acceptable salts, e.g., acid addition salts. For example, pyrido-nitrogeen atoms may form salts with strong acid, while compounds having basic substituerts such as amino groups also form salts with weaker acids. Examples of suitable acids for salt formation are hydrochloric, sulfuric, phosphoric, acetic, citric , oxalic, malonic, salicylic, malic, fumaric, succinic, ascorbic, maleic, methanesuiifonic and other mineral and carboxylic acids well known to those skilled in the art. The salts are prepared by contacting the free base form with a sufficient amount of the desired acid to produce a salt in the conventional manner. The free base forms maay be regenerated by treating the salt with a suitable dilute aqueous base solution s uch as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate. The free base forms differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and baase salts are otherwise equivalent to their respective free base forms for purposes of the invention.

All such acid and base salts are intencled to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponeding compounds for purposes of the invention.

Following are descriptions of the prepaaration of compound I-A using the claimed process.

The following abbreviations are used iin the specification and claims: Ms (methylsulfonyl); Me (methyl); Et (ethyl); LOD (loss on drying); DMAP (4- dimtheylamino-pyridine); and DMSO (dimethayl sulfoxide).

Example 1

Ie

NZ N-N

OO

H3CO

Step a:

HN HN o ace

AT | OT | ed —

HO N mso—/ N° + MeO Va n ia or /\ N _ aan ud N

MeO Va

To a mixture of compound li (200.0 g, 1.0 eq.) and diisopropylethyl amine (280 ml, 1.2 eq.) in CH3CN (600 mi) at °C was slowly added CH3SOCl (112 ml, 1.1 eq.). After the addition was complete, NiaOH (25%, 250 ml) was added at 5°C followed by a solution of compound IVa (34.2g, 1.1eq.) in water (600ml). The reaction mixture was refluxed for 6 h, amd then concentrated to a volume of 800 mi to remove CH;CN. Water (1.2 1) was addexd to the reaction mixture and the batch was cooled to 22°C. The batch was filtered and washed the wet cake with water (600 mi), and dried in a vacuum at 65°C for 24 h. A yellow product was obtained (ca. 415g). "HNMR (CDCl): 7.52 (s, 1H), 6.95 (s, 4H), 5.89 (s, 2H), 4.18 (m, 2H), 4.06 (m, 2H), 3.78 (m, 2H), 3.47 (s, 3H), 3.11 (m, 4H), 2.83 (Mm, 2H), 2.72 (m, 4H).

Step b:

Pa

Ne CN - od 3 ‘sl ve ad ~~ i

A mixture of compound Va (150.0 g, 1.0 eq.), trimethyl orthoformate (120 ml, 2.6 eq.) and a catalytic amount of p-tolmenesulfonic acid in toluene (1.2 1) was heated to a temperature between 105 and 115°C. The reaction mixture was slowly concentrated to 520 ml. The reaction rnixture was then cooled to 15 to 25°C and heptane (1.6 I) was added to complete the precipitation. The batch was filtered, washed with heptane and dried in a va cuum oven at 20 to 30 °C for about 24 h to a

LOD < 0.5%. A light gray product was obtained (ca. 160.8 g).

Mass spectrum: M+1= 413. "HNMR (DMSO): 8.55 (s, 1H), 7.90 (s, 1H), 6.80 (m, 4H), 4.15 (m, 2H), 4.00 (m, 2H), 3.95 (-s, 3H), 3.65 (m, 2H), 3.30 (s, 3H), 2.94 (bs,

~ 13 - 4H), 2.70 (bs, 2H), 2.55 (bs, 4H). BCNMR (DMSO): 1625, 162.4, 150.4, 141.4, 117.6, 115.3, 114.8, 79.7, 70.9, 67.5, 68.5, 56.9, 55.0, 53.0, 49.7, 45.3.

Alternate Step b: : a va pasts av

MeG Vib

A mixture of compound Va (300.0 g, 1.0 eq.), triesthyl orthoformate (280 ml, 2.6 eq.) and a catalytic amount of p-toluenesulfonic acid (3=.0 g) in toluene (1.8 [ was heated to a temperature between 105 and 115°C. The= reaction mixture was slowly concentrated to 1000 ml. The reaction mixture was thesn cooled to 15 to 25°C and heptane (2.1 1) was added to complete the precipitation. The batch was filtered, washed with heptane and dried in a vacuum oven at 2@ to 30 °C forabout24htoa

LOD < 0.5%. A light gray product, Vib, was obtained (ca. 301.2 g).

Mass Spectrum: M+1 = 427. THNMR(DMSO): 8.50 (S , 1H), 7.92 (8S, 1H), 6.81 (m, 4H), 4.35 (m, 2H), 4.10 (t, 2H), 3.99 (m 2H), 3.60 (m, 2H), 3.30 (s, 3H), 2.90 (bs, 4H), 2.50 (m, 4H), 2.70 (t, 2 H), 1.38 (¢, 3H). *CNMR (DMSSO): 162.1, 152.4, 150.6, 145.8, 141.4, 117.6, 115.3, 114.9, 79.770.9, 67.4, 64.71, 58.5, 56.9, 53.0, 49.7,454, 14.2.

Steps c: hat

H \ 1. Isobutyric acid — oY N

MeO IXa

Compound Vla (100 g, 1.0 eq.), compound Vila (2-furoic hydrazide) (28.8 g, 0.97 eq.), toluene (400 ml), and isobutyric acid (23 mH, 1.0 eq.) were combined and the reaction mixture was heated to 50°C and stirred feor over 4 h. The reaction mixture was distilled off to about 300 ml at 50°C. The reaction mixture was heated to 110°C, azeotropic distillation was done to remove thes water generated during the reaction, and then the mbxure was stirred at 110-11 55°C for over 4 h. After cooling to 25°C, the reaction mixture was added to 4.1% HCl solution (450 ml) and heated to reflux. The reaction mixture was stirred at reflux for over 2 h, and then cooled to 25°C. The reaction mixture was settled and the aqu eous layer was separated from the organic layer. The aqueous layer was heated to= 50°C and the pH adjusted to between 1.8 and 2.8. After pH adjustment, the aqueous layer was stirred at 50°C for min, and then slowly cooled to 0°C for over 2 h. The aqueous layer was stirred at 0°C for 1 h to complete the precipitation. The solid ~was filtered and washed with water (250 ml). The product was dried in a vacuum oven at 75-80°C. The product was isolated as a mono-HCI salt and the yield was —110g (82%).

MS: m/z 479, 463, 447, 433, 419, 298, 286, 285, 2.72, 263, 240, 247, 243, 235, 229, 216, 206, 194, 191. 'H NMR (DMSO-de): 58.03 (s , 1H); 7.9 (d, 1H); 7.35 (d, 1H); 7.1 (m, 2H); 6.9 (m, 2H); 6.7 (m, 1H); 4.6 (m, 2H); 4.05- (m, 2H); 3.6 (m, 4H); 3.5 (broad, 6H); 3.3 (s, 3H); 2.5 (m, 2H)

Alternatively, an equivalent amount of comp ound Vib can be substituted for compound Vla to obtain compound Xa.

Step d:

To a mixture of compound Xa (100.0 g, 1.0 eq.) amd KHCOs (40 g, 1.5 eq.) in CH3CN (500 ml) and water (10m) at a temperature between 53 and 58°C was slowly added 2-methoxyphenol cyanate (39.0 g, 1.35 eq.). The reaction mixture was agitated at a temperature between 53 and 58°C for 1 h. Upon completion of the reaction, a 10%

NaOH aqueous solution (200 ml) was added to queench the reaction. The batch was then cooled to a temperature between 20 and 25°«C, and filtered. The cake was washed with water (400ml) and CN3CN (400ml) ard dried in a vacuum oven at 65 to 75°C for about 12 h. A white product was obtained (ca. 91.0g) with about 95% yield.

Mass spectrum: M+1= 504. HNMR (DMSO). 8.387 (s, 1H), 8.13 (bs, 2H), 7.95 (m, 1H), 7.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.3 8 (m, 2H), 4.93(m, 2H), 3.56 (Mm, 2H), 3.37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H), 2.45 (m, 2H).

Example 2 re

NNN

_ SE

OO

HLCO

To a mixture of compound Xa (Example 1, step c) (5%0.0 9, 1.0 eq.) and DMAP (24.0 g, 2.0 eq.) in CH3CN (850 ml) at a temperature between 75 and 85°C was slowly amdded a solution of BrCN (15.0 g, 1.3 eq.) in CH3CN «150.0 ml). The reaction mixture was refluxed for another 3 h. The reaction was cooled to 25°C, and 10%

NaOH ssolution (500 ml) was added to quench the reaction. The batch was filtered, washed with water and dried in a vacuum oven at 65 to 75°C for about 24 h. A light gray product was obtained (ca. 32.0g). .

Mass sspectrum: M+1= 504. "HNMR (DMSO): 8.37 (s, 1H), 8.13 (bs, 2H), 7.95 (m, 1H), 7. 18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3.337 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H), 2.45 (m, 2H).

Example 3

Ire

NZ N-N

SS

OO

H3;CO

To a mixture of compound IXa (Example 1, step c) ( 100.0 g, 1.0 eq.) in THF {500 nl), water (100 ml) and NaOH (50%, 17.0 g) at a tempoerature between 60 and 70°C wwas slowly added a solution of bisphenol-A cyanate ( 30.0 g, 1.1 eq.) in THF (125.0 ml). The reaction mixture was refluxed for another 1 .5 h. The reaction mixture was cooled to 25°C, filtered, washed with water and dried i n a vacuum oven at 65 to 75°C faor about 24 h. A light gray product was obtained (cam. 88.0 g).

Mass spectrum: M+1= 504. "HNMR (DMSO): 8.37 (s, 1 H), 8.13 (bs, 2H), 7.95 (m, 1H), 77.18 (m, 1H), 6.78 (m, 4H), 6.70 (m, 1H), 4.38 (m, 2H), 4.93(m, 2H), 3.56 (m, 2H), 3 .37 (s, 3H), 2.90 (m, 4H), 2.80 (m, 2H), 2.55 (m, 4H) , 2.45 (m, 2H).

While the present invention has been described in conjunction with the specific embocliments set forth above, many alternatives, modifications and variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifi=cations and variations are intended to fall within the sspirit and scope of the presert invention.

Claims

. PCT/US2004/035472 We claim:

1. A process for preparing compounds havirg the structural formula NHz NANI ah Z-Y—X—N N= I or a pharmaceutically acceptable salt thereof , wherein R is R'-furanyl, R'-thienyl, R'-pyridyl, R'—pyridy} N-oxide, R"-oxazolyl, R'*-phenyl, R'-pyrrolyt or cycloalkenyl; X is C,-Cg alkylene; (CH) —a E Y is =N(RYCH2CHN(R®)-, -OCH2CHN(R?)-, -(CHa)-NH-, or (Crs : and Z is R®phenyl, R%-phenylalkyl, R>heteroaryl, diphenylmethyl, R®-C(O)-, Q HN, N= —C— ~ R%-Ss0,-, © or phenyl-CH(OH)-; orwherny Qis H ,Zis also phenylamino or ] pyridylamino; : or Z and Y together are 9 ’ N . N— N= R10 RE (SWC. OC or Rm R'is 1 to 3 substituents independently selected from hydrogen, alkyl, -CF3, halogen, ~NO2, -NR'2R™, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl; R? and R? are independently selected from the group consisting of hydrogen and alkyl; m and n are independently 2-3; Qis AMENDE D SHEET ded de H CN ' OH COCHjs

R* is 1-2 substituents independently selected fron the group consisting of hydrogen and alkyl, or two R* substituents on the same carbon can form =O;

Ris 1 to 5 substituents independently selected fr-om the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkyl-aamino, -CF3, -OCF3, acetyl, -NO 5, hydroxyalkoxy, alkoxyalkoxy, dialkoxy-alkoxy, alkomxy-alkoxy-alkoxy, carboxy- alko xy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-aamino-alkoxy, morpholinyl, alky 1-SO.-, alkyl-SOz-alkoxy, tetrahydropyranyloxy, alkylecarbonyl-atkoxy, alkosxycarbonyl, alkylcarbonyloxy-alkoxy, -SO2NHa, or pienoxy; or adjacent R® substituents together are —0-CHz-0-, -O-CH,CH2-0O-, ~O-CF2-O- or -0-CF,CF>-0- and form a ring with the carbon atoms to which they are attached;

RS is alkyl, R®-phenyl, R>-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)-NH-(C4-Cs)alkyl-, dialkyl-aminomethyl, or

(= alkyl 0 :

R® is 1-2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3 and alkoxy-alkoxy;

R' is 1 to 5 substituents independently selected from the group consisting of hyd rogen, halogen, alkyl, hydroxy, alkoxy, -CN, -NH,, al kylamino, dialkylamino, -CFs3, -OCF; and -S(O)o-zalkyt;

R'is H or alkyl; and

R™ is alkyl-C(OY- or alkyl-SOx-; comprising a) reacting the hydroxyl group of a pyrazole of fomrmula Il

HN con ey { in with an activating agent in the presence of a basee to obtain a compound of formula Il HN oN xd 1 wherein L is a leaving group, and coupling the compound of formula Ill with a cosmpound of formula \Y) Z-Y-H \' in the presence of a base to obtain a compound off formula V HaN CN Z2=Y=X—N_ NZ / b) treating the compound of formula V with trialky=1 orthoformate in the presence of a catalytic amount of an acid to obtaim a compound of formula Vi NZ OR =~" Z=Y=X—N, NW wherein R’ is alky}; c¢) condensing the compound of formula Vi with a hydrazide of formula VII

H.NHN-C(O)-R VII in the presence of an acid to obtain a compound of formula Vili NR NY oll . Z-Y—X-N ‘NZ Vili and hydrolyzing the compound of formula Vill to obtain a compound of formula IX NR HN YY ied Z—-Y—X—N N IX d) cyclizing the compound of formula IX with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the presence of a base.

2. The process of claim 1 for preparing compounds of formula | wherein: R is Rfuranyl, R'-thienyl, R'-pyrrolyl or R"-phenyl; R'is hydrogen or halogen; Xis

(CH / \ TA NN . (CHAS 4 X Lo —N— Ale. . 5 5 ethylene; Yis 2h "R* wherein Q is or ~CH—; Z is R>-phenyl, R™- heteroaryl, RS-C(0)- or R-80,-; and R® is R°-phenyl.

3. The process of claim 2 wherein R is R'-furanyt; R' is h-ydrogen or halogen; Q is i” m amd n are each 2; Ris H; Zis R>-phenyl; and R= is one substituent selected fron the group consisting of alkoxy and alkoxyalkoxy~.

4, The p rocess of claim 2 wherein L is an optionally subsEituted alkylsulfonyl- or arylsulfonyl- group.

5. The perocess of claim 4 wherein Lis a alkylsulfonyl- or =arylsulfonyl- group , selected frorm the group consisting of methanesulfonyl, trifluo romethanesulfonyl, ethanesuifornyl, benzenesulfonyl, p-toluenesulfonyl, p-bromotoenzenesulfonyl and m- nitrobenzenseesulfonyl.

6. The process of claim 5 wherein L is methanesulfonyl.

7. The process of claim 1, step b, wherein the triatky! ortBhoformate is trimethyl orthoformat e.

8. The pprocess of claim 1 wherein the cyanating agent ir step d is a cyanate.

9. The “process of claim 8 wherein the cyanate is selectexd from the group consisting Of 2-methoxyphenyl cyanate, 4-methoxyphenyl cy=anate, 4-phenyiphenyl , cyanate ansd bisphenol A cyanate.

10. The process of claim 9 wherein the cyanate is 2-metihoxyphenyl cyanate.

11. The process of claim 1 for preparing a compound of formula I-A

N¥ NA 7 \ raat am pO H3CO I-A comprising a) reacting the hydroxyl group of a pyrazole of formula Il " CN HO-X—N_ PF N i with rmethanesulfony! chloride in the presence of a base to olotain a compound of formula llla HoN “NON Ne MsO N lla; and coupling the compound of formula fila with a compound of formula IVa 0 YN NH ~~ \/ MeO IVa in thes presence of a base to obtain a compound of formula Wa HN ~ \ N o—~ In Nn— NT ~~ \—/ MeO w/a b) treating the compound of formula Va with trimethyl orthofformate in the pressence of a catalytic amount of an acid to obtain a compo und of formula Via Je N’ ~r™ N OO ~~ \—/ MeO Via c) condensing the compound of formula Via with a hydrazicie of formula Via HJ \ 0] Vila

. : PCT/US200=4/035472 in the presence of &an acid to obtain a compound of formula Villa AD ~ N ~\ N od H+ — N — nn / MeO Villa and hydrolyzing thee compound of formula Villa to obtain a compound of formula 1Xa ML) HN HoN AT N o—{ Nn NZ — n/ MeO Xa d) cyclizing the compound of formula 1Xa with a cyanating agent sel ected from the group conssisting of cyanates and cyanogen halides in the presence of a base.

12. The process of cl aim 11 wherein the cyanating agent is a cyanate selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphenol A cyanate.

13. A process for pre=paring a compound of formula N ‘ad NN R SS =N NG N= or a pharmaceutically acceptable salt thereof, wherein Ris R'-furanyl, RR -thienyl, R'-pyridy}, R'-pyridyl N-oxide, R'-oxazol=y}, R"-phenyl, R'-pyrrolyl «or cycloalkenyl; X is C2-C; alkyle ne; CCH2)m / \ Y is “N(RIICH2CHZN(RY)-, -OCH,CHaN(R?)-, (CHa) NH, or LEH RE, and AMENDED SHEET

Z is R%-phenyl, R®phenylalkyl, R>heteroaryl, diphenylmethyl, R®-C(O)-, Q HN, N— —o

I . R%-80,, © or phenyl-CH(OH)-; or when Q is H |, Z is also phenylamino or pyridylamino; or Z and Y together are 9 ’ N . N— oo! Oy Fe oN R'is 1 to 3 substituents independently selected from hydrogen, alkyl, -CFa, halogen, -NO2, -NR'?R™3, alkoxy, alkylthio, alkylsulfinyl, and alkylsulfonyl; R? and R® are ind ependently selected from the group consisting of hydrogen and alkyl; m and n are independently 2-3; Qis Ra eo a

[3] CN ’' OH COCH; . R* is 1-2 substitu ents independently selected from the group consisting of hydrogen and alkyl, or two R* substituents on the same carbon can form =O; RY is 1 to 5 substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkoxy, -CN, dialkyl-amino, -CF3, -OCF3, acetyl, -NO,, hydroxyalkoxy, al koxyalkoxy, dialkoxy-alkoxy, alkoxy-alkoxy-alkoxy, carboxy- alkoxy, alkoxycarbonylalkoxy, cycloalkyl-alkoxy, dialkyl-amino-alkoxy, morpholinyl, alkyl-SO2-, alkyl-SOz-al koxy, tetrahydropyranyloxy, alkylcarbonyl-alkoxy, alkoxycarbonyl, alkylcarbonyloxy-alkoxy, -SO2NH2, or phenoxy; or adjacent R® substituents together axe ~0-CHz-0-, -O-CH2CH,-O-, ~0-CF2-O- or -O-CF.CF2>-O- and form a ring with thes carbon atoms to which they are attached; R® is alkyl, R5-phenyl, R>-phenylalkyl, thienyl, pyridyl, cycloalkyl, alkyl-OC(O)-NH-C;-Cg)alkyl-, dialkyl-aminomethyl, or

{~ alky-0"S0 : R® is 1-2 groups independently selected from hydrogen, alkyl, hydroxy, alkoxy, halogen, -CF3 and alkoxy-alkoxy; R™ is 1 to § substituents independently selected from the group consisting of hydrogen, halogen, alkyl, hydroxy, alkcoxy, -CN, -NH2, alkylamino, dialkylamino, -CFs3, -OCF3 and -S(O)2alkyl; R'?is H or alkyl; and R" is alkyl-C(O)- or alkyl-SOz-; comprising cyclizing a compound of formula IX nS ied Zo XN, = IX with a cyanating agent selected from the group consisting of cyanates and cyanogen halides in the presence of a base.

14. The process of claim 13 wherein the cyanating agent is a cyanate selected from the group consisting of 2-methoxyphenyl cyanate, 4-methoxyphenyl cyanate, 4-phenylphenyl cyanate and bisphersol A cyanate.

15. The process of claim 13 for pweparing compounds of formula | wherein R is R'-furanyl, R'-thienyl, R'-pyrrolyl or FR"-phenyl; R'is hydrogen or halogen; X is (CH)m I Gl ok othylene; Yis Ch R' whereiinQis “N— or —CH—; Zis R®-phenyl, R°- heteroaryl, R®-C(O)- or R%-80,-; and R® is R*-phenyl.

16. The process of claim 15 wherein R is R"-furanyl; R'is hydrogen or halogen; Q is =; mand n are each 2; R*is H; Z is R®-phenyl; and R® is one substituent selected from the group consisting of alkoxy and atkoxyalkoxy.